Faculty Bibliography

It is well established that chronic food restriction enhances sensitivity to the rewarding and motor-activating effects of abused drugs. However, neuroadaptations underlying these behavioral effects have not been characterized. The purpose of the present study was to explore the possibility that food restriction produces increased dopamine (DA) receptor function that is evident in behavior, signal transduction, and immediate early gene expression. In the first two experiments, rats received intracerebroventricular (i.c.v.) injections of the D1 DA receptor agonist SKF-82958, and the D2/3 DA receptor agonist quinpirole. Both agonists produced greater motor-activating effects in food-restricted than ad libitum-fed rats. In addition, Fos-immunostaining induced by SKF-82958 in caudate-putamen (CPu) and nucleus accumbens (Nac) was greater in food-restricted than ad libitum-fed rats, as was staining induced by quinpirole in globus pallidus and ventral pallidum. In the next two experiments, neuronal membranes prepared from CPu and Nac were exposed to SKF-82958 and quinpirole. Despite the documented involvement of cyclic AMP (cAMP) signaling in D1 DA receptor-mediated c-fos induction, stimulation of adenylyl cyclase (AC) activity by SKF-82958 in CPu and Nac did not differ between groups. Food restriction did, however, decrease AC stimulation by the direct enzyme stimulant, forskolin, but not NaF or MnCl(2), suggesting a shift in AC expression to a less catalytically efficient isoform. Finally, food restriction increased quinpirole-stimulated [(35)S]guanosine triphosphate-gammaS binding in CPu, suggesting that increased functional coupling between D2 DA receptors and G(i) may account for the augmented behavioral and pallidal c-Fos responses to quinpirole. Results of this study support the hypothesis that food restriction leads to neuroadaptations at the level of postsynaptic D1 and D2 receptor-bearing cells which, in turn, mediate augmented behavioral and transcriptional responses to DA. The signaling pathways mediating these augmented responses remain to be fully elucidated

Lateral hypothalamic self-stimulation (LHSS) and the threshold-lowering effects of abused drugs are increased by chronic food restriction. LHSS is also modulated by the endocrine adiposity hormones insulin and leptin. The endogenous melanocortin receptor (MCR) ligands, AGRP (antagonist) and alpha-MSH (agonist) mediate opponent physiological and behavioral actions in response to changes in mediobasal hypothalamic leptin and insulin exposure. The purpose of the present study was to evaluate whether chronic stimulation or blockade of central MCRs alters the rewarding effect of LH stimulation or the threshold-lowering effect of d-amphetamine. Thirty rats were trained in a rate-frequency LHSS paradigm and the threshold-lowering effect of d-amphetamine (0.25 mg/kg, i.p.) was determined. Rats were then divided into 3 groups of 10 and implanted with subcutaneous osmotic minipumps that delivered either the MCR agonist MTII (0.5 mug/12 mul/24 hr), the MCR antagonist SHU9119 (0.5 mug/12 mul/24 hr), or vehicle (12 mul/24 hr) via a lateral ventricular cannula for 12 days. LHSS and the threshold-lowering effect of d-amphetamine were tested again on days 3, 8 and 12 of icv infusions. MTII and SHU9119 produced a sustained decrease and increase, respectively, in food intake. SHU9119 had no effect on LHSS threshold or the threshold-lowering effect of d-amphetamine. MTII, however, lowered LHSS thresholds and augmented the threshold-lowering effect of d-amphetamine. It is not yet clear whether these effects result directly from MCR stimulation or arise secondarily as a consequence of the progressive weight loss produced by MTII infusion

Chronic food restriction increases the rewarding, motor-activating and immediate-early gene responses to centrally injected psychostimulants and direct dopamine (DA) receptor agonists. The purpose of the present study was to determine whether the food restriction regimen that produces these effects causes adaptive changes in D-1 DA receptors and their intracellular signaling pathways. In all experiments, rats were fed 10 grams of chow each day until a 20-25% weight loss was achieved. This was followed by maintenance of the target body weight for at least one additional week. D-1 receptor binding: saturation curves were obtained for specific 3H-SCH23390 binding in caudate-putamen (CPU) and nucleus accumbens (NAC). There were no differences in Kd or Bmax between food-restricted and control subjects. cA

Cocaine and amphetamine regulated transcript (CART) was originally discovered as a novel up-regulated mRNA in a drug abuse paradigm. CART is one of the most abundantly expressed mRNA in the hypothalamus and nucleus accumbens. In rat, differential splicing gives rise to two different CART mRNAs encoding precursors of either 116 or 129 amino acids. CART precursor processing is tissue dependent and two forms of peptide predominate in the brain, CART 55-102 and CART 62-102. Aside from the first report on amphetamine and cocaine as inducers of CART mRNA expression, other studies found modest gender-dependent effects on expression level or no changes at all. The aim of the present study was to re-investigate effects of cocaine on ir-CART peptide levels in the brain using a 'binge' cocaine paradigm. Male rats were treated with 'binge' cocaine for 14 days (3x15 mg/kg/day, i.p.) . One hour after the final injection, levels of ir-CART were quantified by RIA and immunofluorescence. CART immunoreactivity was detected using polyclonal CART antibody as primary and Cy-3-conjugated donkey anti-rabbit secondary antibody. High levels of expression were found in hypothalamic areas and nucleus accumbens and very low levels in caudate putamen, frontal cortex and cerebellum. 'Binge' cocaine caused an increase in the cerebellum, pons, medulla and paraventricular hypothalamic nucleus. Pro-CART processing in 'binge' cocaine treated rats was compared with controls by Western blot analysis. In untreated rats the dominant peptide in all brain structures is CART 55-102. Data on the ratio between the two forms of peptides in cocaine treated rats will be presented

Cocaine-and Amphetamine Regulated Transcript (CART) was first identified as a mRNA upregulated in striatum in response to acute injection of cocaine and amphetamine. The CART transcript encodes for a protein (Pro-CART) which is processed to smaller forms of bioactive peptides, CART 55-102 and CART 62-102. The subcellular localization of CART peptides within dense core vesicles of axon terminals suggests a neurotransmitter role for these peptides. However, CART receptors have not been identified. In the present study, saturable specific binding of (125I) CART was demonstrated in GH3 cells (a rat pituitary adenoma cell line) and bovine anterior pituitary. Further, it was shown by confocal microscopy in live cells that activation of these binding sites results in translocation of beta-arrestin2/green fluorescent protein (beta-arr2-GFP) to the plasma membrane, suggesting that CART binding sites are G-protein coupled receptors. Analysis of receptor-mediated signal transduction revealed that CART peptides inhibit forskolin-stimulated cAMP production in a pertussis toxin-sensitive manner, suggesting that the CART binding site is coupled to Gi/o proteins. CART peptides also activated Mitogen Activated Protein Kinase (MAPK) in a time and dose dependent manner, with significantly different time courses for the 55-102 and 62-102 fragments. Together, these results indicate that cellular effects of CART peptides are mediated by membrane G-protein coupled receptors with negative and positive coupling to cAMP and MAPK signaling pathways, respectively

In an all-male sample of schizophrenic patients stabilized by medication (n=62) and normal controls (n=27), we obtained neuropsychological test data and high-resolution whole brain magnetic resonance scans, as well as detailed psychiatric rating scales on a subset of the patients (n=47). Schizophrenic patients had significantly worse overall age-adjusted cognitive performance than normal controls (average z-score=-0.90, range=-0.60 to -1.81), which included relatively more severe deficits with different types of memory, psychomotor speed, verbal fluency and verbal abstraction. Schizophrenic patients also had significantly smaller bilateral volumes in gray but not white matter in the prefrontal region, superior temporal gyrus and whole temporal lobe, but no group differences were observed in the hippocampus and parahippocampus. Correlations between the brain regions and cognitive performance revealed different sets of significant relationships for the two groups, particularly in the prefrontal and hippocampal regions. In addition, inverse correlations were observed between certain cognitive abilities (psychomotor speed, cognitive flexibility and verbal fluency) and patients' psychiatric ratings, especially with measures of negative symptoms. The convergence of findings for schizophrenic patients regarding the prefrontal region, negative symptoms, psychomotor speed and cognitive flexibility suggests that schizophrenic negative symptoms may involve disruption of frontal-subcortical connections

Three-hundred-eleven female drug-using sex workers in urban Puerto Rico were asked to describe their last negotiation with a client. They described efforts to protect themselves from many hazards of sex work, including violence, illness, and drug withdrawal. They also described efforts to minimize the stigma and marginalization of sex work by cultivating relationships with clients, distinguishing between types of clients, and prioritizing their role as mothers. Sex workers adopted alternating gender roles to leverage autonomy and respect from clients. Their narratives suggest that sex workers negotiate a world in which HIV is relative to other risks, and in which sexual practices which are incomprehensible from an HIV-prevention perspective are actually rooted in a local cultural logic. Future HIV prevention efforts should frame condom use and other self-protective acts in terms that build upon sex workers own strategies for understanding their options and modifying their risks

OBJECTIVE: To evaluate the New York State Expanded Syringe Access Demonstration Program (ESAP) through injection drug user (IDU) surveys, discarded needles and syringes studies, and pharmacy sales and experiences surveys. DESIGN: Pre-post comparison. SETTING: In Harlem, New York City, risk surveys among street-recruited IDUs, needle/syringe street counts on 27 systematically sampled city blocks, and Harlem pharmacist reports of sales and experiences. MAIN OUTCOME MEASURES: Number and types of IDU syringe sources, block mean counts of discarded needles and syringes, level of pharmacy nonprescription syringe sales (NPSS), and pharmacists' experiences. RESULTS: Comparing 209 pre-ESAP with 396 post-ESAP IDUs, pharmacies as a primary syringe source increased: 3.4% to 5.3% (P < .001, and ever pharmacy use increased: 4.9% to 12.5% (P < .001), respectively. Compared with pre-ESAP IDUs, post-ESAP IDUs tended to be younger and more often black. Harlem pharmacy participation in ESAP increased considerably from March 1, 2001, to March 1, 2002, 49% to 79%, respectively. Among three Harlem pharmacies, there was a modest increase in NPSS; pharmacists reported no problems, and no discarded needles and syringes were observed in pharmacy areas. In the three pharmacies, the proportion of syringe sales that were NPSS was 46% (110 to 240 NPSS/month), 3% (25 to 90 NPSS/month), and 0%. The mean ratios of needles/syringes to background trash have not increased in Harlem since ESAP began. CONCLUSION: To date, no evidence of harmful effects discarded needles/syringes, pharmacy altercations) resulting from ESAP were observed. While NPSS have increased in Harlem, pharmacy use among IDUs remains low. In Harlem, efforts are underway to increase ESAP awareness and reduce socioenvironmental barriers to ESAP.

OBJECTIVE: To document changes in pharmacists' opinions and practices from the time of passage to implementation of a law permitting selling syringes without a prescription (the Expanded Syringe Access Demonstration Program [ESAP]). DESIGN: Two cross-sectional randomized telephone surveys. SETTING: High-risk neighborhoods of New York City. SUBJECTS: Pharmacists. MAIN OUTCOME MEASURES: Support for selling syringes without a prescription to injection drug users (IDUs). RESULTS: We completed 130 surveys at baseline (BL) in August 2000, from neighborhoods with high numbers of injection-related acquired immunodeficiency syndrome (AIDS) cases and 231 surveys at law change (LC) in January 2001. To correct for differences in sampling, we limited the analysis to pharmacies in ZIP Codes represented in both samples and weighted results to adjust for the median income level of those postal codes. From BL (n = 83) to LC (n = 84), law awareness increased (43% to 90%, P < .001), as did personal support for selling syringes without a prescription to IDUs (36% to 63%, P < .001). From BL to LC, a larger proportion of supporters believed that selling syringes was an important part of human immunodeficiency virus (HIV) prevention and would help decrease HIV transmission, and a smaller proportion was concerned about customer discomfort and increased drug use. A total of 40% of respondents were ESAP registered at LC but registration was not associated with support for selling syringes to IDUs. CONCLUSIONS: Support for ESAP among pharmacists increased in high-risk neighborhoods as the program was implemented. The finding that some pharmacists were ESAP registered but did not support selling syringes to IDUs and others were supportive, but not ESAP registered, may have program implications.

We evaluated behavior change after disclosure of a positive hepatitis C virus (HCV) antibody test result among a cohort of young injection drug users (IDUs). Participants underwent semiannual interviews, human immunodeficiency virus (HIV) and HCV antibody testing, and pretest and posttest counseling. We used chi(2) statistics to study changes in the frequencies of high-risk behaviors from baseline to a 6-month follow-up visit among 46 IDUs who had a positive HCV test result and among 60 IDUs who did not have a positive HCV test result or who were unaware of their test result. No significant differences were detected between the 2 groups. Both groups continued to share syringes, needles, and other injection paraphernalia. These findings suggest that young IDUs may not be aware of the risk of HCV infection and highlight the urgent need for post-HCV test guidelines and behavioral interventions to reduce ongoing high-risk behavior that perpetuates the risk of HCV transmission.